17-76469184-G-A

Position:

• chr17-76469184-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001088.3(AANAT):​c.175G>A​(p.Val59Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.47

Genes affected

AANAT (HGNC:19): (aralkylamine N-acetyltransferase) The protein encoded by this gene belongs to the acetyltransferase superfamily. It is the penultimate enzyme in melatonin synthesis and controls the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for the function of the circadian clock that influences activity and sleep. This enzyme is regulated by cAMP-dependent phosphorylation that promotes its interaction with 14-3-3 proteins and thus protects the enzyme against proteasomal degradation. This gene may contribute to numerous genetic diseases such as delayed sleep phase syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38902172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AANAT	NM_001088.3	c.175G>A	p.Val59Ile	missense_variant	3/4	ENST00000392492.8
AANAT	NM_001166579.2	c.310G>A	p.Val104Ile	missense_variant	6/7
AANAT	NR_110548.2	n.431G>A		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AANAT	ENST00000392492.8	c.175G>A	p.Val59Ile	missense_variant	3/4	1	NM_001088.3	P1
AANAT	ENST00000250615.7	c.310G>A	p.Val104Ile	missense_variant	6/7	1
AANAT	ENST00000585649.1	c.289G>A	p.Val97Ile	missense_variant	2/3	1
AANAT	ENST00000587798.1	c.231G>A	p.Pro77=	synonymous_variant, NMD_transcript_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251230 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135786

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43 AN XY: 727198

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74478

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000745 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2024

The c.175G>A (p.V59I) alteration is located in exon 3 (coding exon 2) of the AANAT gene. This alteration results from a G to A substitution at nucleotide position 175, causing the valine (V) at amino acid position 59 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.8	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.37	N;N;.
REVEL	Benign	0.23
Sift	Uncertain	0.012	D;T;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.79	.;P;.
Vest4		0.59
MutPred		0.62		.;Gain of glycosylation at S58 (P = 0.067);.;
MVP		0.38
MPC		0.12
ClinPred		0.41	T
GERP RS		4.7
Varity_R		0.084
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373114830; hg19: chr17-74465266; COSMIC: COSV51684197; COSMIC: COSV51684197;